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Introduction

Jacob Raber led this live discussion on 7 May 2004. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Transcript unavailable.

Background

Background Text

This discussion is based on Dr. Raber's recent review for SAGE KE of the same title (Sci. Aging Knowl. Environ., Vol. 2004, Issue 11, pp. re2, 17 March 2004). Note: Alzheimer Research Forum members can access the Full Text.

Increasing evidence indicates that there are reductions in estrogen and androgen levels in aged men and women. These hormonal reductions might be risk factors for cognitive impairments and the development of Alzheimer's disease (AD). Aged people show improved cognition after treatments with sex steroids. Therefore, ongoing clinical AD trials have been designed to evaluate the potential benefits of estrogen therapy in women and testosterone therapy in men. Apolipoprotein E (apoE) plays an important role in the metabolism and redistribution of lipoproteins and cholesterol. The three major human apoE isoforms, apoE2, apoE3, and apoE4, differ in their effects on AD risk and pathology. Here I review various mechanisms proposed to mediate the differential effects of apoE isoforms on brain function and highlight the potential contribution of detrimental isoform-dependent effects of apoE on androgen- and androgen receptor (AR)-mediated pathways. I also discuss potential interactions of androgens with other AD-related factors.

Q&A with Andrea Leblanc and the Alzheimer Research Forum

Q: Estrogen-replacement therapy failed in the Women's Health Study. How could your findings be made clinically useful? Do you envision a better next-generation approach?

A: I think that we can use two approaches to counter the negative effects of hormones. First, using physiological concentrations of hormones (nM range) is sufficient for neuroprotection, as we have shown with primary human neurons. I am not sure if all the clinical trials used higher levels but if so, then maybe smaller doses would be sufficient for the beneficial neuroprotective effect while eliminating the side effects. Second, once we know how hormones induce neuroprotection, we will be able to develop drugs that do not have the side effects due to the multiple actions of the hormones. For example, anything that increases Hsp70 may prove to be an excellent lead compound to prevent intracellular Aβ-mediated neuroprotection.

Q: Do you see a way to activate estrogen/testosterone receptors on neurons in a sufficiently specific way to achieve a therapeutic effect short of flooding the whole body with estrogen or testosterone?

A: Peptidomimetics can be established against one specific action in other receptors with multiple functions. This way the receptor can be stimulated to have only one of its multiple responses. Maybe this approach could be aplied to estrogen/testosterone receptors.

Q: ApoE binds Aβ and is also being studied with regard to its effect on Aβ clearance and deposition. Do you see any connection between this work and yours?

A: ApoE is secreted and will be involved in extracellular Aβclearance but not intracellular Aβ. Unless Apo E can alter metabolism of APP to reduce the amount of intracellular Aβ production, I do not see a connection with our work.

Comments

I am looking forward to this Live Discussion. It may be worthwhile examining other effects of androgens in AD-related problems. Our prior work suggests that intracellular cytosolic Aβ is highly toxic to human neurons (Zhang et al., 2002). Now, we show that physiological concentrations of both estrogen and androgen (testosterone and methyltestosterone) protect against intracellular Aβ toxicity. The protection is complete if neurons are incubated with the hormones for one hour before microinjection of Aβ. We further show that both hormone types work through their respective receptors, that levels of the chaperone Hsp70 increase in estrogen- and androgen-treated neurons, and that Hsp70 can also completely protect against intracellular Aβ toxicity (Zhang et al., 2004). This brings forth another neuroprotective effect of these hormones.